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In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model

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Abstract

Monocarboxylate transporter 1 (MCT1) represents a potential therapeutic target in cancer. The objective of this study was to determine the efficacy of AZD3965 (a specific inhibitor of MCT1) and α-cyano-4-hydroxycinnamic acid (CHC, a nonspecific inhibitor of MCTs) in the murine 4T1 tumor model of triple-negative breast cancer (TNBC). Expression of MCT1 and MCT4 in 4T1 and mouse mammary epithelial cells were determined by Western blot. Inhibition of MCT1-mediated l-lactate uptake and cellular proliferation by AZD3965 and CHC was determined. Mice bearing 4T1 breast tumors were treated with AZD3965 100 mg/kg i.p. twice-daily or CHC 200 mg/kg i.p. once-daily. Tumor growth, metastasis, intra-tumor lactate concentration, immune function, tumor MCT expression, and concentration-effect relationships were determined. AZD3965 and CHC inhibited cell growth and l-lactate uptake in 4T1 cells. AZD3965 treatment resulted in trough plasma and tumor concentrations of 29.1 ± 13.9 and 1670 ± 946 nM, respectively. AZD3965 decreased the tumor proliferation biomarker Ki67 expression, increased intra-tumor lactate concentration, and decreased tumor volume, although tumor weight was not different from untreated controls. CHC had no effect on tumor volume and weight, or intra-tumor lactate concentration. AZD3965 treatment reduced the blood leukocyte count and spleen weight and increased lung metastasis, while CHC did not. These findings indicate AZD3965 is a potent MCT1 inhibitor that accumulates to high concentrations in 4T1 xenograft tumors, where it increases tumor lactate concentrations and produces beneficial effects on markers of TNBC; however, overall effects on tumor growth were minimal and lung metastases increased.

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Abbreviations

MCTs:

Monocarboxylate transporters

TNBC:

Triple-negative breast cancer

CD147:

Basigin

GLUT1:

Glucose transporter 1

CHC:

Alpha-cyano-4-hydroxycinnamic acid

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Funding

This work was funded by the National Institute of Health National Institute on Drug Abuse (grant DA023223). X.G. was funded in part by an Allen Barnett Fellowship.

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Author notes

  1. Xiaowen Guan

    Present address: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Redwood City, California, 94063, USA

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 304 Pharmacy Building, Buffalo, New York, 14214, USA

    Xiaowen Guan & Marilyn E. Morris

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  1. Xiaowen Guan
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  2. Marilyn E. Morris
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Contributions

Participated in research design: Guan and Morris

Conducted experiments: Guan

Contributed new reagents or analytic tools: Guan and Morris

Performed data analysis: Guan and Morris

Wrote or contributed to the writing of the manuscript: Guan and Morris

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Correspondence to Marilyn E. Morris.

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Guan, X., Morris, M.E. In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model. AAPS J 22, 84 (2020). https://doi.org/10.1208/s12248-020-00466-9

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